WO2009153461A2 - Novel method for the synthesis of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one, and use in the synthesis of ivabradine and of addition salts thereof with a pharmaceutically acceptable acid - Google Patents

Novel method for the synthesis of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one, and use in the synthesis of ivabradine and of addition salts thereof with a pharmaceutically acceptable acid Download PDF

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WO2009153461A2
WO2009153461A2 PCT/FR2009/000738 FR2009000738W WO2009153461A2 WO 2009153461 A2 WO2009153461 A2 WO 2009153461A2 FR 2009000738 W FR2009000738 W FR 2009000738W WO 2009153461 A2 WO2009153461 A2 WO 2009153461A2
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WO2009153461A3 (en
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Jean-Michel Lerestif
Jean-Pierre Lecouve
Daniel Brigot
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Les Laboratoires Servier
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines

Definitions

  • the present invention relates to a process for the synthesis of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one of formula (I), and its application to the synthesis of ivabradine, its addition salts with a pharmaceutically acceptable acid and their hydrates.
  • Ivabradine as well as its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride, have very interesting pharmacological and therapeutic properties, especially bradycardic properties, which render these compounds useful in the treatment or prevention of different clinical situations myocardial ischemia such as angina pectoris, myocardial infarction and associated rhythm disorders, as well as in various pathologies including rhythm disorders, especially supraventricular, and in heart failure.
  • the present invention relates to a process for synthesizing the compound of formula (I):
  • the groups R 1 and R 2 which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1, 3-dioxolane or 1,3-dioxepane, which is subjected to an acid cyclization reaction to conduct after isolation the compound of formula (I).
  • the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by preliminary transformation of the compound of formula (IV) into a compound of formula (VI):
  • X represents a halogen atom or a group OCOR 3 where R 3 is a linear or branched (C 1 -C 6 ) alkyl group, a phenyl group, a benzyl group or an imidazole group,
  • groups R 1 and R 2 which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1, 3-dioxolane or 1,3-dioxepane,
  • the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by reaction with a compound of formula (VII):
  • groups R 1 and R 2 which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1,3-dioxolane or 1,3-dioxepane,
  • organic solvents that can be used for the condensation reaction of the compound of formula (VII) with the compound of formula (IV) in the presence of a coupling agent, mention may be made, without limitation, of toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and 90 dioxane.
  • the compound of formula (V) is not isolated.
  • the compound of formula (VI) is not isolated.
  • the group X in the compound of formula (VI) preferably represents a chlorine atom.
  • organic solvents that can be used for the reaction of conversion of the compound of formula (IV) into a compound of formula (VI)
  • organic solvents there may be mentioned, without limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, , 2- 100 dichloroethane, chloroform and dioxane.
  • the preferred organic solvent for the reaction of conversion of the compound of formula (IV) into a compound of formula (VI) is dichloromethane.
  • the temperature of the reaction of conversion of the compound of formula (IV) into compound of formula (VI) is preferably between 20 and 40 ° C.
  • the reagent preferentially used to carry out the conversion of the compound of formula (IV) into a compound of formula (VI) for which X represents a chlorine atom is thionyl chloride.
  • the amount of thionyl chloride involved in the conversion reaction of the compound of formula (IV) into a compound of formula (VI) is preferably between 1 and 1.3 moles per mole of compound of formula (IV).
  • organic solvents that can be used for the reaction between the compound of formula (VI) and the compound of formula (VII)
  • 2-dichloroethane, chloroform and dioxane mention may be made, without limitation, of toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, and the like.
  • 2-dichloroethane 2-dichloroethane, chloroform and dioxane.
  • the preferred organic solvent for the reaction between the compound of formula (VI) and the compound of formula (VII) is dichloromethane.
  • the temperature of the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably between 0 and 40 ° C.
  • the amount of compound of formula (VII) involved in the reaction with the compound of formula (VI) is preferably between 1 and 1.2 moles per mole of compound of formula (VI).
  • the amount of base used in the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably between 1 and 1.3 moles per mole of compound of formula (VI).
  • the base preferably used for the reaction between the compound of formula (VI) and the compound of formula (VII) is triethylamine.
  • acids that can be used to effect the cyclization of the compound of formula (V) to a compound of formula (I) mention may be made, without limitation, of concentrated sulfuric acid, polyphosphoric acid and concentrated hydrochloric acid in solution. aqueous concentrated hydrochloric acid in solution in acetic acid, hydrobromic acid 135 concentrated in solution in acetic acid and methanesulfonic acid.
  • the amount of acid involved in the cyclization reaction of the compound of formula (V) with a compound of formula (I) is preferably between 5 and 15 moles per mole of compound of formula (V).
  • the temperature of the cyclization reaction in an acidic medium of the compound of formula (V) is preferably between 0 and 40 ° C.
  • the acid preferentially used to cyclize the compound of formula (V) to a compound of formula (I) is concentrated sulfuric acid.
  • the amount of concentrated sulfuric acid used in the cyclization reaction of the compound of formula (V) is preferably between 1.5 and 3 milliliters per gram of acid ( 3,4-dimethoxyphenyl) acetic acid of formula (IV).
  • the compound of formula (I) obtained according to the process of the present invention is particularly useful as a synthesis intermediate in the synthesis of ivabradine, its addition salts with a pharmaceutically acceptable acid and its hydrates.
  • R 4 and R 5 which may be identical or different, each represent a linear or branched (C 1 -C 6 ) alkoxy group or together with the carbon atom which carries them A 1,3-dioxane or 1,3-dioxolane ring, and Y represents a halogen atom, preferably a bromine atom, or a tosylate, mesylate or triflate group,
  • ivabradine which is reacted with (7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] -N-methylmethanamine under reductive amination conditions, to lead to ivabradine, which may optionally be converted into its addition salts with a pharmaceutically acceptable acid, chosen from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic and malonic acids, succinic, glutaric, fiimaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic and camphoric, and their hydrates.
  • a pharmaceutically acceptable acid chosen from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic and malonic acids, succinic, glutaric, fiimaric
  • CDI carbonyldiimidazole 175
  • DABCO 1,4-diazabicyclo [2.2.2] octane
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • HBTU O- (benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium hexafluorophosphate
  • TBTU O- (benzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate 190
  • T3P n-propane phosphonic anhydride
  • Stage A (3,4-dimethoxyphenyl) acetic acid chloride
  • load 135 g of (3,4-dimethoxyphenyl) acetic acid and 270 ml of dichloromethane then bring the temperature of the reaction medium to reflux and add dropwise 90 g of thionyl chloride. Stir the mixture at reflux for 3 h. The resulting solution is used as for the next step.
  • the product is obtained by precipitation in a water / NMP (4/1) mixture, filtration and drying with a yield of 92.9% relative to (3,4-dimethoxyphenyl) acetic acid and a chemical purity greater than 99.5%.

Abstract

Method for the synthesis of the compound of formula (I). Use in the synthesis of ivabradine, of addition salts thereof with a pharmaceutically acceptable acid, and of hydrates thereof.

Description

NOUVEAU PROCEDE DE SYNTHESE DE LA 7,8-DIMETHOXY-l,3-DIHYDRO- NOVEL PROCESS FOR THE SYNTHESIS OF 7,8-DIMETHOXY-1,3-DIHYDRO-
2//-3-BENZAZEPIN-2-ONE, ET APPLICATION A LA SYNTHESE DE2 // - 3-BENZAZEPIN-2-ONE, AND APPLICATION TO THE SYNTHESIS OF
L'IVABRADINE ET DE SES SELS D'ADDITION A UN ACIDEIVABRADIN AND ITS SALTS OF ADDITION TO ACID
PHARMACEUTIQUEMENT ACCEPTABLEPHARMACEUTICALLY ACCEPTABLE
La présente invention concerne un procédé de synthèse de la 7,8-diméthoxy-l,3-dihydro- 2H-3-benzazépin-2-one de formule (I), et son application à la synthèse de l'ivabradine, de ses sels d'addition à un acide pharmaceutiquement acceptable et des leurs hydrates.The present invention relates to a process for the synthesis of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one of formula (I), and its application to the synthesis of ivabradine, its addition salts with a pharmaceutically acceptable acid and their hydrates.
Figure imgf000002_0001
Figure imgf000002_0001
Le composé de formule (I) obtenu selon le procédé de l'invention est utile dans la synthèse de l'ivabradine de formule (II)The compound of formula (I) obtained according to the process of the invention is useful in the synthesis of ivabradine of formula (II)
Figure imgf000002_0002
ou 3-{3-[{[(75)-3,4-diméthoxybicyclo[4.2.0]octa-l,3,5-trién-7-yl]méthyl}(méthyl)amino] propyl}-7,8-diméthoxy-l,3,4,5-tétrahydro-2H-3-benzazépin-2-one,
Figure imgf000002_0002
or 3- {3 - [{[(75) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl} (methyl) amino] propyl} -7.8 dimethoxy-l, 3,4,5-tetrahydro-2H-3-benzazepin-2-one,
de ses sels d'addition à un acide pharmaceutiquement acceptable et de leurs hydrates.of its addition salts with a pharmaceutically acceptable acid and their hydrates.
L'ivabradine, ainsi que ses sels d'addition à un acide pharmaceutiquement acceptable, et plus particulièrement son chlorhydrate, possèdent des propriétés pharmacologiques et thérapeutiques très intéressantes, notamment des propriétés bradycardisantes, qui rendent ces composés utiles dans le traitement ou la prévention des différentes situations cliniques d'ischémie myocardique telles que l'angine de poitrine, l'infarctus du myocarde et les troubles du rythme associés, ainsi que dans les différentes pathologies comportant des troubles du rythme, notamment supra-ventriculaires, et dans l'insuffisance cardiaque.Ivabradine, as well as its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride, have very interesting pharmacological and therapeutic properties, especially bradycardic properties, which render these compounds useful in the treatment or prevention of different clinical situations myocardial ischemia such as angina pectoris, myocardial infarction and associated rhythm disorders, as well as in various pathologies including rhythm disorders, especially supraventricular, and in heart failure.
La préparation et l'utilisation en thérapeutique de l'ivabradine et de ses sels d'addition à un acide pharmaceutiquement acceptable, et plus particulièrement de son chlorhydrate, ont été décrits dans le brevet européen EP 0 534 859.The preparation and therapeutic use of ivabradine and its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride, have been described in European Patent EP 0 534 859.
Ce brevet décrit la synthèse du chlorhydrate de l'ivabradine à partir du composé de formule (III) :This patent describes the synthesis of ivabradine hydrochloride from the compound of formula (III):
Figure imgf000003_0001
Figure imgf000003_0001
et fait référence à la publication J. Med. Chem 1990, Vol. 33 (5), 1496-1504 pour la préparation de ce composé.and refers to J. Med. Chem 1990, Vol. 33 (5), 1496-1504 for the preparation of this compound.
La voie de synthèse du composé de formule (III) décrite dans cette publication utilise une réaction d'alkylation du composé de formule (I) :The route of synthesis of the compound of formula (III) described in this publication uses an alkylation reaction of the compound of formula (I):
Figure imgf000003_0002
Figure imgf000003_0002
La publication précitée décrit la préparation du composé de formule (I) en utilisant comme intermédiaire le iV-(2,2-diméthoxyéthyl)-2-(3,4-diméthoxyphényl)-acétamide obtenu à partir de l'acide (3,4-diméthoxyphényl) acétique. La cyclisation du phénylacétamide obtenu se fait en présence de l'acide chlorhydrique dans l'acide acétique, pour conduire au composé de formule (I) avec un rendement global de 58% par rapport à l'acide (3,4- diméthoxyphényl)acétique.The above publication describes the preparation of the compound of formula (I) using as intermediate the N- (2,2-dimethoxyethyl) -2- (3,4-dimethoxyphenyl) -acetamide obtained from the acid (3,4). -dimethoxyphenyl) acetic acid. The cyclization of the phenylacetamide obtained is in the presence of hydrochloric acid in acetic acid, to lead to compound of formula (I) with an overall yield of 58% relative to (3,4-dimethoxyphenyl) acetic acid.
Compte-tenu de l'intérêt industriel de l'ivabradine et de ses sels, il était impératif de trouver un procédé performant permettant notamment d'accéder à la 7,8-diméthoxy-l,3- dihydro-2H-3-benzazépin-2-one de formule (I) avec un excellent rendement.In view of the industrial interest of ivabradine and its salts, it was imperative to find a high-performance process allowing in particular access to 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine. 2-one of formula (I) with excellent yield.
Or, la Demanderesse s'est aperçue que de manière surprenante, en utilisant des conditions opératoires spécifiques, il était possible d'obtenir à l'échelle industrielle le composé de formule (I) avec un rendement supérieur à 92% et une pureté chimique supérieure à 99,5%.However, the Applicant has found that surprisingly, using specific operating conditions, it was possible to obtain on an industrial scale the compound of formula (I) with a yield greater than 92% and a higher chemical purity. at 99.5%.
Plus spécifiquement, la présente invention concerne un procédé de synthèse du composé de formule (I) :More specifically, the present invention relates to a process for synthesizing the compound of formula (I):
Figure imgf000004_0001
Figure imgf000004_0001
caractérisé en ce que l'acide (3,4-diméthoxyphényl) acétique de formule (IV)characterized in that (3,4-dimethoxyphenyl) acetic acid of formula (IV)
Figure imgf000004_0002
Figure imgf000004_0002
est transformé en composé de formule (V)is converted into a compound of formula (V)
Figure imgf000004_0003
dans laquelle les groupements Ri et R2, identiques ou différents, représentent des groupements alkoxy (Ci-C6) linéaires ou ramifiés, ou bien forment ensemble avec l'atome de carbone qui les porte un cycle 1,3-dioxane, 1,3-dioxolane ou 1,3-dioxépane, lequel est soumis à une réaction de cyclisation en milieu acide pour conduire après isolement au composé de formule (I).
Figure imgf000004_0003
in which the groups R 1 and R 2 , which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1, 3-dioxolane or 1,3-dioxepane, which is subjected to an acid cyclization reaction to conduct after isolation the compound of formula (I).
Dans l'un des modes de réalisation préférés de l'invention, la transformation du composé de formule (IV) en composé de formule (V) est effectuée par transformation préliminaire du composé de formule (IV) en composé de formule (VI) :In one of the preferred embodiments of the invention, the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by preliminary transformation of the compound of formula (IV) into a compound of formula (VI):
Figure imgf000005_0001
dans laquelle X représente un atome d'halogène ou un groupement OCOR3 où R3 est un groupement alkyle (Ci-C6) linéaire ou ramifié, un groupement phényle, un groupement benzyle ou un groupement imidazole,
Figure imgf000005_0001
in which X represents a halogen atom or a group OCOR 3 where R 3 is a linear or branched (C 1 -C 6 ) alkyl group, a phenyl group, a benzyl group or an imidazole group,
dans un solvant organique,in an organic solvent,
puis le composé de formule (VI) est soumis à une réaction de condensation avec un composé de formule (VII) :then the compound of formula (VI) is subjected to a condensation reaction with a compound of formula (VII):
Figure imgf000005_0002
Figure imgf000005_0002
dans laquelle les groupements Ri et R2, identiques ou différents, représentent des groupements alkoxy (Ci-C6) linéaires ou ramifiés, ou bien forment ensemble avec l'atome de carbone qui les porte un cycle 1,3-dioxane, 1,3-dioxolane ou 1,3-dioxépane,in which the groups R 1 and R 2 , which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1, 3-dioxolane or 1,3-dioxepane,
en présence d'une base dans un solvant organique, pour conduire au composé de formule (V) :in the presence of a base in an organic solvent, to yield the compound of formula (V):
Figure imgf000006_0001
Figure imgf000006_0001
Dans un autre mode de réalisation préféré de l'invention, la transformation du composé de formule (IV) en composé de formule (V) est effectuée par réaction avec un composé de formule (VII) :In another preferred embodiment of the invention, the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by reaction with a compound of formula (VII):
Figure imgf000006_0002
Figure imgf000006_0002
75 dans laquelle les groupements Ri et R2, identiques ou différents, représentent des groupements alkoxy (C]-C6) linéaires ou ramifiés, ou bien forment ensemble avec l'atome de carbone qui les porte un cycle 1,3-dioxane, 1,3-dioxolane ou 1,3-dioxépane,In which the groups R 1 and R 2 , which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1,3-dioxolane or 1,3-dioxepane,
en présence d'un agent de couplage dans un solvant organique,in the presence of a coupling agent in an organic solvent,
pour conduire au composé de formule (V) :to yield the compound of formula (V):
Figure imgf000006_0003
Figure imgf000006_0003
Parmi les agents de couplage pouvant être utilisés pour la réaction de condensation du composé de formule (VII) sur le composé de formule (IV), on peut citer à titre non limitatif les réactifs ou couples de réactifs suivants : EDCI, EDCI/HOBT, EDCI/HOAT, EDCI/NHS, DCC, DCC/HOBT, DCC/HOAT, DCC/NHS, HATU, HBTU, TBTU, BOP,Among the coupling agents that can be used for the condensation reaction of the compound of formula (VII) with the compound of formula (IV), mention may be made, without limitation, of the following reagents or couples of reagents: EDCI, EDCI / HOBT, EDCI / HOAT, EDCI / NHS, DCC, DCC / HOBT, DCC / HOAT, DCC / NHS, HATU, HBTU, TBTU, BOP,
85 PyBOP, CDI, T3P. Parmi les solvants organiques pouvant être utilisés pour la réaction de condensation du composé de formule (VII) sur le composé de formule (IV) en présence d'un agent de couplage, on peut citer à titre non limitatif le toluène, le dichlorométhane, le 2- méthyltétrahydrofurane, le chlorobenzène, le 1 ,2-dichloroéthane, le chloroforme et le 90 dioxane.85 PyBOP, CDI, T3P. Among the organic solvents that can be used for the condensation reaction of the compound of formula (VII) with the compound of formula (IV) in the presence of a coupling agent, mention may be made, without limitation, of toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-dichloroethane, chloroform and 90 dioxane.
Dans l'un des modes de réalisation préférés de l'invention, le composé de formule (V) n'est pas isolé.In one of the preferred embodiments of the invention, the compound of formula (V) is not isolated.
Dans l'un des modes de réalisation préférés de l'invention, le composé de formule (VI) n'est pas isolé.In one of the preferred embodiments of the invention, the compound of formula (VI) is not isolated.
95 Le groupement X dans le composé de formule (VI) représente préférentiellement un atome de chlore.The group X in the compound of formula (VI) preferably represents a chlorine atom.
Parmi les solvants organiques pouvant être utilisés pour la réaction de transformation du composé de formule (IV) en composé de formule (VI), on peut citer à titre non limitatif le toluène, le dichlorométhane, le 2-méthyltétrahydrofurane, le chlorobenzène, le 1,2- 100 dichloroéthane, le chloroforme et le dioxane.Among the organic solvents that can be used for the reaction of conversion of the compound of formula (IV) into a compound of formula (VI), there may be mentioned, without limitation, toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, , 2- 100 dichloroethane, chloroform and dioxane.
Le solvant organique préféré pour la réaction de transformation du composé de formule (IV) en composé de formule (VI) est le dichlorométhane.The preferred organic solvent for the reaction of conversion of the compound of formula (IV) into a compound of formula (VI) is dichloromethane.
La température de la réaction de transformation du composé de formule (IV) en composé de formule (VI) est préférentiellement comprise entre 20 et 40°C.The temperature of the reaction of conversion of the compound of formula (IV) into compound of formula (VI) is preferably between 20 and 40 ° C.
105 Le réactif préférentiellement utilisé pour réaliser la transformation du composé de formule (IV) en composé de formule (VI) pour lequel X représente un atome de chlore est le chlorure de thionyle. La quantité de chlorure de thionyle engagée dans la réaction de transformation du composé de formule (IV) en composé de formule (VI) est préférentiellement comprise entre 1 et 1 ,3 moles par mole de composé de formule (IV).The reagent preferentially used to carry out the conversion of the compound of formula (IV) into a compound of formula (VI) for which X represents a chlorine atom is thionyl chloride. The amount of thionyl chloride involved in the conversion reaction of the compound of formula (IV) into a compound of formula (VI) is preferably between 1 and 1.3 moles per mole of compound of formula (IV).
Parmi les solvants organiques pouvant être utilisés pour la réaction entre le composé de formule (VI) et le composé de formule (VII), on peut citer à titre non limitatif le toluène, le dichlorométhane, le 2-méthyltétrahydrofurane, le chlorobenzène, le 1 ,2-dichloroéthane, le chloroforme et le dioxane.Among the organic solvents that can be used for the reaction between the compound of formula (VI) and the compound of formula (VII), mention may be made, without limitation, of toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, and the like. , 2-dichloroethane, chloroform and dioxane.
Le solvant organique préféré pour la réaction entre le composé de formule (VI) et le composé de formule (VII) est le dichlorométhane.The preferred organic solvent for the reaction between the compound of formula (VI) and the compound of formula (VII) is dichloromethane.
La température de la réaction entre le composé de formule (VI) et le composé de formule (VII) est préférentiellement comprise entre 0 et 40°C.The temperature of the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably between 0 and 40 ° C.
La quantité de composé de formule (VII) engagée dans la réaction avec le composé de formule (VI) est préférentiellement comprise entre 1 et 1,2 moles par mole de composé de formule (VI).The amount of compound of formula (VII) involved in the reaction with the compound of formula (VI) is preferably between 1 and 1.2 moles per mole of compound of formula (VI).
La quantité de base engagée dans la réaction entre le composé de formule (VI) et le composé de formule (VII) est préférentiellement comprise entre 1 et 1 ,3 moles par mole de composé de formule (VI).The amount of base used in the reaction between the compound of formula (VI) and the compound of formula (VII) is preferably between 1 and 1.3 moles per mole of compound of formula (VI).
Parmi les bases qui peuvent être utilisées pour la réaction entre le composé de formule (VI) et le composé de formule (VII), on peut citer à titre non limitatif la pyridine, la DMAP et les aminés tertiaires, par exemple la triéthylamine, la DIEA, la N-méthylpipéridine, la DBU, le DABCO, le DBN et la N-méthylmorpholine.Among the bases which can be used for the reaction between the compound of formula (VI) and the compound of formula (VII), mention may be made, without limitation, of pyridine, DMAP and tertiary amines, for example triethylamine, DIEA, N-methylpiperidine, DBU, DABCO, DBN and N-methylmorpholine.
La base préférentiellement utilisée pour la réaction entre le composé de formule (VI) et le composé de formule (VII) est la triéthylamine. Parmi les acides pouvant être utilisés pour effectuer la cyclisation du composé de formule (V) en composé de formule (I), on peut citer à titre non limitatif l'acide sulfurique concentré, l'acide polyphosphorique, l'acide chlorhydrique concentré en solution aqueuse, l'acide chlorhydrique concentré en solution dans l'acide acétique, l'acide bromhydrique 135 concentré en solution dans l'acide acétique et l'acide méthanesulfonique.The base preferably used for the reaction between the compound of formula (VI) and the compound of formula (VII) is triethylamine. Among the acids that can be used to effect the cyclization of the compound of formula (V) to a compound of formula (I), mention may be made, without limitation, of concentrated sulfuric acid, polyphosphoric acid and concentrated hydrochloric acid in solution. aqueous concentrated hydrochloric acid in solution in acetic acid, hydrobromic acid 135 concentrated in solution in acetic acid and methanesulfonic acid.
La quantité d'acide engagée dans la réaction de cyclisation du composé de formule (V) en composé de formule (I) est préférentiellement comprise entre 5 et 15 moles par mole de composé de formule (V).The amount of acid involved in the cyclization reaction of the compound of formula (V) with a compound of formula (I) is preferably between 5 and 15 moles per mole of compound of formula (V).
La température de la réaction de cyclisation en milieu acide du composé de formule (V) est 140 préférentiellement comprise entre 0 et 400C.The temperature of the cyclization reaction in an acidic medium of the compound of formula (V) is preferably between 0 and 40 ° C.
L'acide préférentiellement utilisé pour effectuer la cyclisation du composé de formule (V) en composé de formule (I) est l'acide sulfurique concentré.The acid preferentially used to cyclize the compound of formula (V) to a compound of formula (I) is concentrated sulfuric acid.
Lorsque les intermédiaires réactionnels ne sont pas isolés au cours du procédé, la quantité d'acide sulfurique concentrée engagée dans la réaction de cyclisation du composé de 145 formule (V) est préférentiellement comprise entre 1,5 et 3 millilitres par gramme d'acide (3,4-diméthoxyphényle) acétique de formule (IV).When the reaction intermediates are not isolated during the process, the amount of concentrated sulfuric acid used in the cyclization reaction of the compound of formula (V) is preferably between 1.5 and 3 milliliters per gram of acid ( 3,4-dimethoxyphenyl) acetic acid of formula (IV).
Le composé de formule (I) obtenu selon le procédé de la présente invention est particulièrement utile comme intermédiaire de synthèse dans la synthèse de l'ivabradine, de ses sels d'addition à un acide pharmaceutiquement acceptable et de ses hydrates.The compound of formula (I) obtained according to the process of the present invention is particularly useful as a synthesis intermediate in the synthesis of ivabradine, its addition salts with a pharmaceutically acceptable acid and its hydrates.
150 A titre d'exemple, Palkylation du composé de formule (I) par un composé de formule (VIII) :By way of example, the alkylation of the compound of formula (I) by a compound of formula (VIII):
Figure imgf000009_0001
dans laquelle R4 et R5 , identiques ou différents, représentent chacun un groupement alkoxy (Ci-C6) linéaire ou ramifié, ou bien forment ensemble avec l'atome de carbone qui les porte 155 un cycle 1,3-dioxane ou 1,3-dioxolane, et Y représente un atome d'halogène, préférentiellement un atome de brome, ou un groupement tosylate, mésylate ou triflate,
Figure imgf000009_0001
in which R 4 and R 5 , which may be identical or different, each represent a linear or branched (C 1 -C 6 ) alkoxy group or together with the carbon atom which carries them A 1,3-dioxane or 1,3-dioxolane ring, and Y represents a halogen atom, preferably a bromine atom, or a tosylate, mesylate or triflate group,
conduit au composé de formule (IX)leads to the compound of formula (IX)
Figure imgf000010_0001
dont l'hydrogénation catalytique conduit au composé hydrogéné correspondant de formule (X) :
Figure imgf000010_0001
whose catalytic hydrogenation leads to the corresponding hydrogenated compound of formula (X):
Figure imgf000010_0002
Figure imgf000010_0002
dans laquelle R4 et R5 sont tels que définis dans la formule (VIII),in which R 4 and R 5 are as defined in formula (VIII),
dont la déprotection du diacétal conduit à l'aldéhyde de formule (XI)whose deprotection of the diacetal leads to the aldehyde of formula (XI)
Figure imgf000010_0003
Figure imgf000010_0003
qui est mis en réaction avec la (7S)-3,4-diméthoxybicyclo[4.2.0]octa-l,3,5-trién-7-yl]-./V- 165 méthylméthanamine dans des conditions d'amination réductrice, pour conduire à l'ivabradine, qui peut éventuellement être transformée en ses sels d'addition à un acide pharmaceutiquement acceptable, choisi parmi les acides chlorhydrique, bromhydrique, sulfurique, phosphorique, acétique, trifluoroacétique, lactique, pyruvique, malonique, succinique, glutarique, fiimarique, tartrique, maléïque, citrique, ascorbique, oxalique, 170 méthanesulfonique, benzènesulfonique et camphorique, et en leurs hydrates.which is reacted with (7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] -N-methylmethanamine under reductive amination conditions, to lead to ivabradine, which may optionally be converted into its addition salts with a pharmaceutically acceptable acid, chosen from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic and malonic acids, succinic, glutaric, fiimaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic and camphoric, and their hydrates.
Lexique des abréviations utilisées :Glossary of abbreviations used:
BOP : benzotriazol-l-yl-oxy-tris-(diméthylamino)-phosphonium hexafluorophosphateBOP: benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate
CDI : carbonyldiimidazole 175 DABCO : l,4-diazabicyclo[2.2.2]octaneCDI: carbonyldiimidazole 175 DABCO: 1,4-diazabicyclo [2.2.2] octane
DBN : l,5-diazabicyclo[4.3.0]non-5-èneDBN: 1,5-diazabicyclo [4.3.0] non-5-ene
DBU : l,8-diazabicyclo[5.4.0]undec-7-èneDBU: 1,8-diazabicyclo [5.4.0] undec-7-ene
DCC : dicyclohexylcarbodiimideDCC: dicyclohexylcarbodiimide
DIEA : iV,jV-diisopropyléthylamine 180 DMAP : 4-diméthylaminopyridineDIEA: N, N-diisopropylethylamine 180 DMAP: 4-dimethylaminopyridine
EDCI: 1 -(3-diméthylaminopropyl)-3-éthyl-carbodiimide chlorhydrateEDCI: 1- (3-Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride
HATU: O-(7-azabenzotriazol-l-yl)-l,l,3,3-tétraméthyluronium hexafluorophosphateHATU: O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
HBTU: O-(benzotriazol- 1 -yl)- 1 , 1 ,3,3-tétraméthyluronium hexafluorophosphateHBTU: O- (benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium hexafluorophosphate
HOAT: 1 -hydroxy-7-azabenzotriazole 185 HOBT : 1 -hydroxybenzotriazoleHOAT: 1-hydroxy-7-azabenzotriazole 185 HOBT: 1-hydroxybenzotriazole
NHS : N-hydroxysuccinimideNHS: N-hydroxysuccinimide
NMP : iV-méthylpyrrolidoneNMP: N-methylpyrrolidone
PyBOP : O-(benzotriazol-l-yl)-oxytripyrrolidinophosphonium hexafluorophosphatePyBOP: O- (benzotriazol-1-yl) -oxytripyrrolidinophosphonium hexafluorophosphate
TBTU : O-(benzotriazol-l-yl)-l,l,3,3-tétraméthyluronium tétrafluoroborate 190 T3P : n-propane phosphonic anhydrideTBTU: O- (benzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate 190 T3P: n-propane phosphonic anhydride
L'exemple ci-dessous illustre l'invention.The example below illustrates the invention.
Préparation de la 7,8-diméthoxy-l,3-dihydro-2H-3-beDzazépin-2-onePreparation of 7,8-dimethoxy-1,3-dihydro-2H-3-beZazazin-2-one
Stade A : Chlorure de l 'acide (3, 4-diméthoxyphényl) acétique Dans un réacteur, charger 135g d'acide (3,4-diméthoxyphényl) acétique et 270 ml de 195 dichlorométhane puis amener la température du milieu réactionnel à reflux et ajouter goutte à goutte 90g de chlorure de thionyle. Agiter le mélange à reflux pendant 3 h. La solution obtenue est utilisée telle que pour l'étape suivante.Stage A: (3,4-dimethoxyphenyl) acetic acid chloride In a reactor, load 135 g of (3,4-dimethoxyphenyl) acetic acid and 270 ml of dichloromethane then bring the temperature of the reaction medium to reflux and add dropwise 90 g of thionyl chloride. Stir the mixture at reflux for 3 h. The resulting solution is used as for the next step.
Stade B : N-(2, 2-diméthoxyéthyl)-2-(3, 4-diméthoxyphényl)acétamideStage B: N- (2,2-dimethoxyethyl) -2- (3,4-dimethoxyphenyl) acetamide
200 Dans un réacteur, charger 225ml de dichlorométhane, 44,15g de 2,2-diméthoxyéthylamine et 44,35g de triéthylamine puis refroidir le milieu à 10°C et ajouter goutte à goutte 237,4g de la solution obtenue à l'étape précédente (correspondant à 75g d'acide (3,4- diméthoxyphényl) acétique) en maintenant la température masse à 10°C. Agiter le mélange 2h à 15°C. La solution obtenue est utilisée telle que pour l'étape suivante.200. In a reactor, load 225 ml of dichloromethane, 44.15 g of 2,2-dimethoxyethylamine and 44.35 g of triethylamine and then cool the medium to 10 ° C. and dropwise add 237.4 g of the solution obtained in the previous step. (corresponding to 75 g of (3,4-dimethoxyphenyl) acetic acid) while maintaining the temperature mass at 10 ° C. Stir the mixture for 2 h at 15 ° C. The resulting solution is used as for the next step.
205 Stade C : 7,8-diméthoxy-l,3-dihydro-2H-3-bemazépin-2-oneStage C: 7,8-dimethoxy-1,3-dihydro-2H-3-bemazepin-2-one
Dans un réacteur contenant la solution obtenue à l'étape précédente et refroidi à 10°C, ajouter 150ml d'acide sulfurique 36N en maintenant la température en dessous de 20°C. Agiter le mélange à 15-20°C pendant 1Oh puis laisser décanter le milieu réactionnel et recueillir la phase acide sulfurique contenant le produit.In a reactor containing the solution obtained in the preceding step and cooled to 10 ° C., add 150 ml of 36N sulfuric acid while maintaining the temperature below 20 ° C. Stir the mixture at 15-20 ° C for 10 h and then decant the reaction medium and collect the sulfuric acid phase containing the product.
210 Le produit est obtenu par précipitation dans un mélange eau/NMP (4/1), filtration et séchage avec un rendement de 92,9% par rapport à l'acide (3,4-diméthoxyphényl) acétique et une pureté chimique supérieure à 99,5%. The product is obtained by precipitation in a water / NMP (4/1) mixture, filtration and drying with a yield of 92.9% relative to (3,4-dimethoxyphenyl) acetic acid and a chemical purity greater than 99.5%.

Claims

REVENDICATIONS
1. Procédé de synthèse du composé de formule (I) :1. Process for synthesizing the compound of formula (I):
Figure imgf000013_0001
Figure imgf000013_0001
caractérisé en ce que l'acide (3,4-diméthoxyphényl) acétique de formule (IV)characterized in that (3,4-dimethoxyphenyl) acetic acid of formula (IV)
Figure imgf000013_0002
Figure imgf000013_0002
est transformé en composé de formule (V)is converted into a compound of formula (V)
Figure imgf000013_0003
Figure imgf000013_0003
220 dans laquelle les groupements Ri et R2, identiques ou différents, représentent des groupements alkoxy (Ci-C6) linéaires ou ramifiés, ou bien forment ensemble avec l'atome de carbone qui les porte un cycle 1,3-dioxane, 1,3-dioxolane ou 1,3-dioxépane,220 in which the groups R 1 and R 2 , which are identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups, or together form with the carbon atom carrying them a 1,3-dioxane ring, , 3-dioxolane or 1,3-dioxepane,
lequel est soumis à une réaction de cyclisation en milieu acide pour conduire après isolement au composé de formule (I). which is subjected to an acid cyclization reaction to conduct after isolation the compound of formula (I).
225 2. Procédé de synthèse selon la revendication 1, caractérisé en ce que la transformation du composé de formule (IV) en composé de formule (V) est effectuée par transformation préliminaire du composé de formule (IV) en composé de formule (VI) :2. Synthesis process according to claim 1, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by preliminary transformation of the compound of formula (IV) into a compound of formula (VI) :
Figure imgf000014_0001
Figure imgf000014_0001
dans laquelle X représente un atome d'halogène ou un groupement OCOR3 où R3 est un 230 groupement alkyle (Ci-C6) linéaire ou ramifié, un groupement phényle, un groupement benzyle ou un groupement imidazolyle,in which X represents a halogen atom or an OCOR 3 group where R 3 is a linear or branched (C 1 -C 6 ) alkyl group, a phenyl group, a benzyl group or an imidazolyl group,
dans un solvant organique,in an organic solvent,
puis le composé de formule (VI) est soumis à une réaction de condensation avec un composé de formule (VII) :then the compound of formula (VI) is subjected to a condensation reaction with a compound of formula (VII):
Figure imgf000014_0002
Figure imgf000014_0002
dans laquelle les groupements Ri et R2, identiques ou différents, représentent des groupements alkoxy (Ci-C6) linéaires ou ramifiés, ou bien forment ensemble avec l'atome de carbone qui les porte un cycle 1,3-dioxane, 1,3-dioxolane ou 1,3-dioxépane,in which the groups R 1 and R 2 , which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1, 3-dioxolane or 1,3-dioxepane,
en présence d'une base dans un solvant organique,in the presence of a base in an organic solvent,
240 pour conduire au composé de formule (V) :240 to yield the compound of formula (V):
Figure imgf000014_0003
Figure imgf000014_0003
3. Procédé de synthèse selon la revendication 1 , caractérisé en ce que la transformation du composé de formule (IV) en composé de formule (V) est effectuée par réaction avec un composé de formule (VII) :3. Synthesis process according to claim 1, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out by reaction with a compound of formula (VII):
Figure imgf000015_0001
Figure imgf000015_0001
dans laquelle les groupements Ri et R2, identiques ou différents, représentent des groupements alkoxy (Ci-C6) linéaires ou ramifiés, ou bien forment ensemble avec l'atome de carbone qui les porte un cycle 1,3-dioxane, 1,3-dioxolane ou 1,3-dioxépane,in which the groups R 1 and R 2 , which may be identical or different, represent linear or branched (C 1 -C 6 ) alkoxy groups or, together with the carbon atom carrying them, form a 1,3-dioxane ring, 1, 3-dioxolane or 1,3-dioxepane,
en présence d'un agent de couplage dans un solvant organique,in the presence of a coupling agent in an organic solvent,
250 pour conduire au composé de formule (V) :250 to yield the compound of formula (V):
Figure imgf000015_0002
Figure imgf000015_0002
4. Procédé de synthèse selon la revendication 2, caractérisé en ce que les composés de formules (V) et (VI) ne sont pas isolés.4. Synthesis process according to claim 2, characterized in that the compounds of formulas (V) and (VI) are not isolated.
5. Procédé de synthèse selon la revendication 3, caractérisé en ce que le composé de 255 formule (V) n'est pas isolé.5. Synthesis process according to claim 3, characterized in that the compound of formula (V) is not isolated.
6. Procédé de synthèse selon l'une quelconque des revendications 2 ou 4, caractérisé en ce que, dans le composé de formule (VI), X représente un atome de chlore. 6. Synthesis process according to any one of claims 2 or 4, characterized in that, in the compound of formula (VI), X represents a chlorine atom.
7. Procédé de synthèse selon l'une quelconque des revendications 2, 4 ou 6, caractérisé en ce que le solvant utilisé pour la transformation du composé de formule (IV) en7. Synthesis process according to any one of claims 2, 4 or 6, characterized in that the solvent used for the conversion of the compound of formula (IV) into
260 composé de formule (VI) est le dichlorométhane.260 compound of formula (VI) is dichloromethane.
8. Procédé de synthèse selon l'une quelconque des revendications 2, 4, 6 ou 7, caractérisé en ce que la température de réaction de transformation du composé de formule (IV) en composé de formule (VI) est comprise entre 200C et 400C.8. Synthesis process according to any one of claims 2, 4, 6 or 7, characterized in that the reaction temperature of conversion of the compound of formula (IV) to compound of formula (VI) is between 20 0 C and 40 ° C.
9. Procédé de synthèse selon l'une quelconque des revendications 2, 4 ou 6 à 8, 265 caractérisé en ce que le réactif utilisé pour la transformation du composé de formule9. Synthesis process according to any one of claims 2, 4 or 6 to 8, characterized in that the reagent used for the transformation of the compound of formula
(IV) en composé de formule (VI) est le chlorure de thionyle.(IV) the compound of formula (VI) is thionyl chloride.
10. Procédé de synthèse selon la revendication 9, caractérisé en ce que la quantité de chlorure de thionyle engagée dans la réaction de transformation du composé de formule (IV) en composé de formule (VI) est comprise entre 1 et 1,3 moles par mole10. Synthesis process according to claim 9, characterized in that the amount of thionyl chloride involved in the reaction of conversion of the compound of formula (IV) to a compound of formula (VI) is between 1 and 1.3 moles per mole
270 de composé de formule (IV).270 of compound of formula (IV).
11. Procédé de synthèse selon l'une quelconque des revendications 2, 4 ou 6 à 10, caractérisé en ce que le solvant de la réaction entre les composés de formule (VI) et (VII) est le dichlorométhane.11. Synthesis process according to any one of claims 2, 4 or 6 to 10, characterized in that the solvent for the reaction between the compounds of formula (VI) and (VII) is dichloromethane.
12. Procédé de synthèse selon l'une quelconque des revendications 2, 4 ou 6 à 1 1, 275 caractérisé en ce que la température de la réaction entre les composés de formule (VI) et (VII) est comprise entre 0 et 400C.12. Synthesis process according to any one of claims 2, 4 or 6 to 11, characterized in that the temperature of the reaction between the compounds of formula (VI) and (VII) is between 0 and 40 0. vs.
13. Procédé de synthèse selon l'une quelconque des revendications 2, 4 ou 6 à 12, caractérisé en ce que la quantité de composé (VII) engagée dans la réaction avec le composé de formule (VI) est comprise entre 1 et 1,2 moles par mole de composé de13. Synthesis process according to any one of claims 2, 4 or 6 to 12, characterized in that the amount of compound (VII) involved in the reaction with the compound of formula (VI) is between 1 and 1, 2 moles per mole of compound of
280 formule (VI). 280 formula (VI).
14. Procédé de synthèse selon l'une quelconque des revendications 2, 4 ou 6 à 13, caractérisé en ce que la quantité de base engagée dans la réaction entre les composés de formule (VI) et (VII) est comprise entre 1 et 1 ,3 moles par mole de composé (VI).14. Synthesis process according to any one of claims 2, 4 or 6 to 13, characterized in that the amount of base involved in the reaction between the compounds of formula (VI) and (VII) is between 1 and 1 3 moles per mole of compound (VI).
15. Procédé de synthèse selon l'une quelconque des revendications 2, 4 ou 6 à 14, 285 caractérisé en ce que la base utilisée dans la réaction entre les composés de formule15. Synthesis process according to any one of claims 2, 4 or 6 to 14, characterized in that the base used in the reaction between the compounds of formula
(VI) et (VII) est la pyridine, la DMAP ou une aminé tertiaire.(VI) and (VII) is pyridine, DMAP or a tertiary amine.
16. Procédé de synthèse selon la revendication 15, caractérisé en ce que la base utilisée dans la réaction entre les composés de formule (VI) et (VII) est la triéthylamine.16. Synthesis process according to claim 15, characterized in that the base used in the reaction between the compounds of formula (VI) and (VII) is triethylamine.
17. Procédé de synthèse selon l'une quelconque des revendications 1 à 16, caractérisé en 290 ce que la quantité d'acide engagée dans la réaction de cyclisation du composé de formule (V) est comprise entre 5 et 15 moles par mole de composé de formule (V).17. Synthesis process according to any one of claims 1 to 16, characterized in that the amount of acid involved in the cyclization reaction of the compound of formula (V) is between 5 and 15 moles per mole of compound of formula (V).
18. Procédé de synthèse selon l'une quelconque des revendications 1 à 17, caractérisé en ce que la température de la réaction de cyclisation en milieu acide du composé de formule (V) est comprise entre 0 et 40°C.18. Synthesis process according to any one of claims 1 to 17, characterized in that the temperature of the acid cyclization reaction of the compound of formula (V) is between 0 and 40 ° C.
295 19. Procédé de synthèse selon l'une quelconque des revendications 1 à 18, caractérisé en ce que l'acide utilisé pour la cyclisation du composé de formule (V) est l'acide sulfurique concentré.19. Synthesis process according to any one of claims 1 to 18, characterized in that the acid used for the cyclization of the compound of formula (V) is concentrated sulfuric acid.
20. Procédé de synthèse selon les revendications 4 ou 5 et 19, caractérisé en ce que la quantité d'acide sulfurique concentré engagée dans la réaction de cyclisation du20. Synthesis process according to claims 4 or 5 and 19, characterized in that the amount of concentrated sulfuric acid involved in the cyclization reaction of
300 composé de formule (V) est comprise entre 1,5 et 3 millilitres par gramme d'acide300 compound of formula (V) is between 1.5 and 3 milliliters per gram of acid
(3,4-diméthoxyphényl) acétique de formule (IV).(3,4-dimethoxyphenyl) acetic acid of formula (IV).
21. Procédé de synthèse de l'ivabradine et de ses sels pharmaceutiquement acceptables, dans lequel le composé de formule (IV) est transformé en composé de formule (I)21. Process for the synthesis of ivabradine and its pharmaceutically acceptable salts, in which the compound of formula (IV) is converted into a compound of formula (I)
305 selon le procédé de la revendication 1 , puis le composé de formule (I) est transformé en ivabradine, qui peut éventuellement être transformée en ses sels d'addition à un acide pharmaceutiquement acceptable, choisi parmi les acides chlorhydrique, bromhydrique, sulfurique, phosphorique, acétique, trifluoroacétique, lactique, pyruvique, malonique, succinique, glutarique, fumarique, tartrique, maléïque, citrique, ascorbique, oxalique, méthanesulfonique, benzènesulfonique et camphorique, et en leurs hydrates. 305 according to the process of claim 1, then the compound of formula (I) is converted into ivabradine, which can optionally be converted into its pharmaceutically acceptable acid selected from hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic and camphoric acids, and their hydrates.
PCT/FR2009/000738 2008-06-20 2009-06-19 Novel method for the synthesis of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one, and use in the synthesis of ivabradine and of addition salts thereof with a pharmaceutically acceptable acid WO2009153461A2 (en)

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WO2011098582A2 (en) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Novel forms of ivabradine hydrochloride
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US10221141B2 (en) 2015-06-03 2019-03-05 Urquima, S.A. Method for the preparation of highly pure ivabradine base and salts thereof

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